Conformational Analysis

Conformational analysis
• The different arrangements of the atoms in space that result from rotations of
groups about single bonds are called conformations of the molecule.
•An analysis of the energy changes that a molecule undergoes as groups rotate
about single bonds is called conformational analysis.

Different conformations Different configurations

Conformations of ethane
 Torsion or Dihedral angle

The single parameter differentiating such conformers is an angle between two

planes that contain atoms ABC and BCD in themselves. This dihedral angle ω is
called a "torsion" angle and is most frequently used for specification of the type of
conformations.
 Types of Strain
• Steric - Destabilization due to the repulsion
between the electron clouds of atoms or groups.
Groups try to occupy some common space.
• Torsional - Destabilization due to the repulsion
between pairs of bonds caused by the
electrostatic repulsion of the electrons in the
bonds. Groups are eclipsed.
• Angle - Destabilisation due to distortion of a
bond angle from it's optimum value caused by
the electrostatic repulsion of the electrons in the
bonds. e.g. cyclopropane
 Potential energy of ethane as function of torsion angles

•staggered conformation has potential energy minimum

•eclipsed conformation has potential energy maximum
• staggered conformation is lower in energy than the eclipsed by
2.9 kcal/mole (12 kJ/mole)
 Why is the eclipsed conformation higher in energy
than the staggered conformation?

•The H-atoms are too small to get in each other’s

way-steric factors make up < 10% of the rotational
barrier in ethane
 Torsional strain
Caused by repulsion of the bonding electrons of one substituent with the bonding
electrons of a nearby substituent

filled orbitals repel

▪ Stabilizing interaction between filled

C-H σ bond and empty C-H σ *
antibonding bonding orbital

The real picture is probably a mixture of all 3 effects

• The rotational barrier is (12 kJ/mol) small enough to allow the conformational isomers
to interconvert million of times per second
 Conformations of butane

B D

Potential energy of butane as a function of torsion angle

A “synclinal” or “gauche”
B “anticlinal”
C “anti-periplanar” or “anti”
D “syn-periplanar” or “fully eclipsed
 C “anti-periplanar” or “anti”
No torsional strain as the groups are staggered and CH3 groups are
par apart

A “synclinal” or “gauche”
van der Waals forces between two CH3 groups are repulsive: the
electron clouds repel each other which accounts for 0.9
Kcal/mole more energy compared to anti conformer

B “anticlinal”
• Calculations reveal that at room temperature ~72% of the molecules of
butane torsional
are in thestrain andconformation,
“anti” large van der waals repulsive
28% are forces
in “gauche”
between the H and CH3 groups
conformation

D “syn-periplanar” or “fully eclipsed

Highest energy due to torsional strain and large van der

waals repulsive force between the CH3 groups
n-Butane Torsional Energy Profile
Butane in “Chair” Form
 Conformations and Conformers

Butane can exit in an infinite number of conformations (6 most important have

been considered), but has only 3 conformers (potential energy minima)-the two
“gauche”conformations and the “anti” conformations

• The preference for a staggered conformation causes carbon chains to orient

themselves in a zig zag fashion, see structure of decane
n-Pentane
The Syn-Pentane Conformation
 The syn-Pentane Interaction - Consequences

Using our knowledge of acyclic conformational analysis, we can predict the

conformation found in the crystal state of a bourgeanic acid derivative.
 The syn-Pentane Interaction - Consequences

Using our knowledge of acyclic conformational analysis, we can predict the

conformation found in the crystal state of a bourgeanic acid derivative.
 Conformations of 2,3-dimethylbutane

# One achiral anti form

# Two enantiomeric Gauche forms
# Equally populated, Gauche = 2 x anti
Conformations of mono/poly halogenoalkanes
 Conformations of mono/poly halogenoalkanes

# In the gaseous state anti is predominant (steric and electronic)

# In the Liquid state (in polar solvent of high dielectric constant) gauche forms
have significant population
Conformations of vicinal-dihalogeno compounds
 Conformations and H-bonding

# Intramolecular H-bonding (vicinal groups); stability (8-20 kJ/mol)

# For effective H-bonding, donor and acceptor must be close enough (either eclipsed
or Gauche)
# In eclipsed, however atoms come within contact distance, so VDW repulsive forces
make them unstable
# In gauche (torsion angle of 60-70 o) ideally suited for intra-H bonding, predominant
conformer
 Conformations and H-bonding

The intramolecular H-bond is always

stronger in the d/l (and racemic) forms,
they are more stable than the meso
isomers

The intramolecular H-bonding in d/l form is stronger than in the meso form
Saturated Cyclic Compounds
 Cyclopropane
Angle and Torsional Strain
 Cyclic compounds twist and bend to minimize the 3 different kinds of strain
1. Angle strain 2. Torsional strain 3. Steric strain

Cyclopropane
• banana bonds
poor orbital overlap
HCH 115°

Electron density diverts away

from the ring by 21°
•Torsional strain

For sp3: 25% s & 75% p charector

Here the four hybrid orbitals of C are far from Good overlap
equivalent Strong bond

External orbitals: 33% s & 67% p sp2

Internal orbitals: 17% s & 83% p sp5
Poor overlap
Weak bond
 Cyclobutane

to reduce torsional angle

Cyclobutane
Interplanar angle 35°
Cyclobutane
 Cyclopentane

Envelope Half chair

The energy difference is little

•one carbon atom is bent upwards
•The molecule is flexible and shifts conformation constantly
•Hence each of the carbons assume the pivotal position in rapid
succession .
•The additional bond angle strain in this structure is more than
compensated by the reduction in eclipsed hydrogens.
•With little torsional strain and angle strain, cyclopentane is as stable
as cyclohexane.
 Cyclopentane

n Two lowest energy conformations of cyclopentane (10 envelope and 10 half chair conformations)
differ by only 0.5 kcal/mol. They are in rapid conformational flux (pseudorotation) which causes the
molecule to appear to have a single out-of-plane atom "bulge" which rotates about the ring.

n Since there is no "natural" conformation of cyclopentane, the ring conforms to minimize interactions
of any substituents present.
 Cyclohexane

Chair conformation

Sum of the van der Waals radii = 2.4 A0

Boat conformation

Newman projection of the

boat conformation
How to Draw a
Chair Conformation

all opposite bonds

are parallel
Ring flipping or
inversion
 Interconversions of Cyclohexane

Chair Half boat Twist boat boat

Erel=0.0 kcal/mol Erel=10 Erel=5.5 Erel=6.5

Twist boat Half boat Opposite sense Chair

Opposite sense

Planar Erel= very large >20 kcal/mol

Rings can Flip from one Chair Conformation to Another
Rings can Flip from one Chair Conformation to Another
 Cyclohexane energy profile for cyclohexane ring reversal

Half chair Half chair

Δ
H 1-1.15
boat
(4.2-6.3)

Twist boat

chair chair
• The energy difference between the chair, boat, and twist conformation of
cyclohexane are low enough to make their separation impossible at r.t. At room
temperature approx. 1 million introversions occur each other second.
• More than 99% of the molecules are estimated to be in chair conformation at any
given time
 Flipping Chair Conformations
• All axial bonds become equatorial
• All equatorial bonds become axial
• All “up” bonds stay up
• All “down” bonds stay down
Axial-up becomes Equatorial-up
 Monosubstituted cyclohexane

This conformation is lower in energy

Why?
When X=CH3, conformer with Me in axial is higher in
energy by 7.3 kJ/mol than the corresponding equatorial
conformer.
Result: 20:1 ratio of equatorial:axial conformer at 200 C

1,3-diaxial interaction
The black bonds are anti-
periplanar
(only one pair shown)

The black bonds are synclinal

(gauche)
(only one pair shown)
X Equilibrium Energy diff. between % with
constant axial and equatorial substitutent
conformers equatorial
kJ/mol
H 1 0 50
Me 19 7.3 95
Et 20 7.5 95
i-Pr 42 9.3 98
t-Bu >3000 >20 >99
OMe 2.7 2.5 73
Ph 110 11.7 99
 1,2-symmetrically disubstituted cyclohexane

Diastereomeric, chiral and therefore resolvable

Enontiomeric, chiral and not resolvable

It exists as a dl-pair, but since barrier to rotation is low to allow separation.

Therefore the (±)- pair is inseparable and hence the compound is optically inactive.
 A closer look of 1,2-symmetrically di-substituted cyclohexane

Planar structure
shows cis is meso
and achiral

They are non-superposable

mirror images and constitutes a
pair of rapidly interconvertible
enantiomers
1,3-symmetrically disubstituted cyclohexane

Diastereomers, achiral

Identical, chiral

cis-isomer is stable than trans isomer

 Topoisomerisation process (ring flipping leads to identical compounds)

# Trans 1,3-di-symmetrically substituted cyclohexane exists in a resolvable pair

# Ring inversion (flipping) converts (+) into (+) and (-) into (-) enantiomers. This is
called topoisomerisation process
1,4-symmetrically disubstituted cyclohexane

Identical, achiral

Diastereomers, achiral

Both have plane of symmetry, achiral

Trans is stable than cis

 Relative population of 1,2-dihalo cyclohexanes

# The population of diaxial conformer increases across Cl<Br<I (as size increases)
# The population of di-equatorial conformer is high in solvent of high dielectric
constant (such as benzene, dioxane)
Concept of locking group in conformational analysis
 Preferred Conformations

Disfavoured

t-butyl group
a locking group

Twist boat
Write preferred conformation for
Conformational preferences of 1,2 or 1,3-ditertbutyl cyclohexanes (presence of 2 locking groups)
Conformational preferences of intramolecular H-bonding and dipole-dipole repulsion
Rigid molecules from cyclohexane conformers
Conformational equilibrium in 1-phenyl-1-methyl cyclohexane
Conformational preferences can be modulated under forced reaction condition
Conformational Analysis of Bicyclic Systems
Bicyclic Systems
Identify the chair or boat-six membered rings in the following structures
Draw stable conformations for the following compounds